Scientists spotlight salutogenesis and the TCF7 gene as powerful tools to fight inflammation, boost longevity, and prevent age-related disease.

Study: The 15-Year Survival Advantage: Immune Resilience as a Salutogenic Force in Healthy Aging. Image Credit: ORION PRODUCTION / Shutterstock.com

A recent Aging Cell study examines how salutogenesis, the active production of health through immune resilience (IR), resists disease.

What is salutogenesis?

Inflammatory processes are essential to protect host organisms against infection and other invading pathogens. Despite its important role in maintaining homeostasis, dysregulated immune function can increase the risk of various diseases including cancer. This dichotomous nature of inflammation as both a defender and potential driver of disease underlies its complex role in health and disease.

To elucidate the role between aging, mortality and immunity, the researchers of the current study developed an integrated four-dimensional evolutionary framework that considers immune robustness, inflammatory stressors, salutogenesis, and immune resistance (IR).  

Immune robustness refers to the ability of hosts to neutralizes pathogens while minimizing tissue damage, inflammatory stressors activate immune responses. In the event that immune robustness fails, chronic low-grade inflammation, which is often referred to as inflammaging, immune senescence, and accumulation of senescent cells can arise, all of which accelerate biological aging and morbidity.

Salutogenesis encompasses the different cellular mechanisms that counteract aging-related pathologies to increase an individual’s lifespan. Thus, premature mortality could be driven by the failure to sustain salutogenic adaptations.

About the study

The current study included blood samples obtained from approximately 17,500 participants who were exposed to various inflammatory challenges throughout their lifespan. Both CD8+ and CD4+ T-cell levels were measured from these samples to classify each individual’s immune health grade (IHG). Both IHGs and the presence of IR-associated gene expression signatures were used to quantify each individual’s IR.

Gene expression signatures were categorized as positive or negative salutogenesis readouts. Positive salutogenesis readouts reflected gene expression signatures that were associated with slower immune aging, extended lifespan, and the presence of immunocompetence-related genes. Comparatively, negative salutogenesis comprised gene signatures associated with increased inflammaging, senescent cell burden, and increased expression of inflammation-related genes.

The impact on both IR metrics and salutogenesis status was then correlated with clinical health outcomes among a cohort of individuals with and without a history of the coronavirus disease 2019 (COVID-19).

Immune resislience, TCF7, and the prevention of age-related diseases

The pathogenic triad arises due to compromised IR integrity during lifelong stress responses, rather than chronological aging alone. For example, a 40-year-old individual with poor IR had a 9.7-fold greater risk of mortality, which is equivalent to that of a 55.5-year-old with optimal IR.

Genomic screening of 1,380 transcription factors led to the identification of transcription factor 7 (TCF7)-centered regulatory network-driven IR mechanisms and six co-regulated factors. TCF7 encodes TCF1, which is a regulator of T-cell immunity and stemness.

A clinically actionable salutogenic trait was established through maintaining optimal IR with TCF7 levels, which was referred to as optimal IR-TCF7^high. The presence of this salutogenic trait significantly reduced the emergence of the pathogenic triad, which subsequently prevented age-associated immunopathologies such as an increased risk of cardiovascular disease, severe infection, and mortality. These findings demonstrate that salutogenesis is fundamental to extending disease-free lifespan and longevity.

IR-TCF7^high status was directly attributed to components of the insulin-like growth factor (IGF) system, which is a highly evolutionarily conserved signaling pathway that is implicated in both aging phenotypes and longevity.  

In a proof-of-concept experiment, the researchers explored the potential effects of anti-inflammatory agents targeting tumor necrosis factor α (TNFα) and anti-α₄β₇ integrin to restoring IR-TCF7^high expression. These studies demonstrated the efficacy of a TNFα antagonist in mitigating IR degradation while simultaneously reducing pathogenic triad burden, thus demonstrating the potential utility of immunomodulatory agents in preventing IR dysfunction.

Our research identifies IR degradation as an age-independent, inflammatory stress-dependent accelerator of aging phenotypes.”

Conclusions

IR confers survival advantages by integrating adaptive and innate immunity to mitigate the effects of immune aging, cellular senescence, and chronic inflammation, all of which contribute to mortality and aging. Optimal IR has the potential to facilitate youthful immune profiles at any age, enhance vaccine responses, and reduce age-related disease burdens, including cardiovascular and Alzheimer’s disease.